"The region of DNA implicated in our study contains six genes. We don't know which of those genes is most likely to harbor this particular risk factor for Alzheimer's disease, but we're getting closer. We're now trying to nail down which one of these six genes is the most likely to be involved."

By Washington University School of Medicine, [RxPG] An international team of researchers, led by investigators at Washington University School of Medicine in St. Louis, are zeroing in on a gene that increases risk for Alzheimer's disease. They have identified a region of chromosome 10 that appears to be involved in risk for the disease that currently affects an estimated 4.5 million Americans.

"There are a few genes that have been implicated in the development of early-onset Alzheimer's disease, but other than APOE, no genes have been found that increase risk for the more common, late-onset form of the disease," says principal investigator Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry at Washington University. "The region of DNA identified in our study showed evidence of replication in four independent series of experiments. I haven't seen a putative risk factor show such consistent results since the e4 variant of the APOE gene was identified as a risk factor for late-onset Alzheimer's disease more than 10 years ago."

In the January issue of the American Journal of Human Genetics, Goate's team of researchers reports results of a scan of more than 1,400 single-nucleotide polymorphisms (SNPs) on chromosome 10 to home in on susceptibility genes for late-onset Alzheimer's disease.

A SNP is an area of DNA where a change has occurred. A strand of DNA consists of four chemical bases, or nucleotides, represented by the letters A, C, G and T. When several regions of DNA from a population are compared, sites where variations exist may be found. Some individuals will have the original base, and others will have a variant. That site where a difference can be identified is called a single nucleotide polymorphism, or SNP.

Since most DNA does not make proteins, the majority of SNPs have no effect on DNA function or on health and disease. However, some SNP variants can cause major health problems. An example is APOE4, a common SNP in the apolipoprotein E gene that increases risk for Alzheimer's disease.

Goate and colleagues have not yet isolated a gene on chromosome 10, but in studying the 1,400 SNPs on chromosome 10 in DNA from three series, each with approximately 400 people with late-onset Alzheimer's disease and 400 healthy, age-matched controls, her team found only one SNP that consistently showed evidence of risk for Alzheimer's disease in all three series.

"The region of DNA implicated in our study contains six genes," Goate says. "We don't know which of those genes is most likely to harbor this particular risk factor for Alzheimer's disease, but we're getting closer. We're now trying to nail down which one of these six genes is the most likely to be involved."

Goate expects between five and 10 genes eventually will be implicated as possible risk factors for late-onset Alzheimer's disease, and she says it's possible that more than one of those genes is located on chromosome 10.

"One thing we're trying to do at a functional level is to see whether any of the six genes that we've identified might be involved in pathways that we already know are related to Alzheimer's disease," she says. "For example, we know amyloid-beta peptide plays a role, so we want to see whether any of these genes might have a role in amyloid-beta metabolism.

"We don't really know the nature of this risk factor yet. What we can say is that we believe we know where it's located, and we know there are six genes in that region. But there also could be other regulatory elements within that strand of DNA that don't directly produce a protein but may somehow affect proteins produced elsewhere in the genome. At this point, we can say that there is a variant in this region of DNA that is increasing risk for Alzheimer's disease, but we can't yet say how," Goate says.

This research was supported by the National Institute on Aging of the National Institutes of Health, Celera Diagnostics and the Medical Research Council, U.K.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

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